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Method of detecting and evaluating angiotensinogen receptor-modulating compounds using placental cells

a technology of angiotensinogen receptor and placental cells, which is applied in the field of detecting and evaluating angiotensinogen receptormodulating compounds using placental cells, can solve the problems of inability to definitively answer the question whether agt is produced by placental tissue, the production of agt protein itself, and the identification of a renin-angiotensinogen receptor in native human placental cells

Inactive Publication Date: 2007-07-31
MARSHFIELD CLINIC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention is about a method for screening substances for their ability to interact with a specific receptor called the AGT receptor, which is found in placental cells. This method involves contacting the cells with a labeled version of the substance and measuring the amount of labeled substance that binds to the cells. By comparing the results to a standard curve, the receptor-modulatory activity of the substance can be determined. The invention has the advantage of using human cells, which makes the results more relevant to in vivo situations."

Problems solved by technology

The question, however, of whether AGT is produced by placental tissue has not yet been answered conclusively.
However, neither the production of the AGT protein itself, nor the identification of a renin-angiotensinogen receptor, has been documented in native human placental cells.
Although these drugs (and many other ACE-inhibitors) are already in commercial use, they have undesirable side effects.
Only those candidate compounds that pass the initial screening are advanced to far more expensive animal testing.

Method used

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  • Method of detecting and evaluating angiotensinogen receptor-modulating compounds using placental cells
  • Method of detecting and evaluating angiotensinogen receptor-modulating compounds using placental cells
  • Method of detecting and evaluating angiotensinogen receptor-modulating compounds using placental cells

Examples

Experimental program
Comparison scheme
Effect test

example 1

AGT Binding

[0035]Labeled AGT, 3 μg, was added to each well containing 1 ml DEME and 2-3×104 cells. The cells were harvested at 5 min, and 2, 4, 8, 16 and 24 h, washed five times with DEME, lysed in a buffer containing 0.1 mol / L Tris, 2 mmol / L EDTA, 1% Triton-X 100, 1 μmol / L DTT, pH 7.8, and the radioactivity of the whole lysate measured. Each experiment contained two duplicates and the reported values are the mean of two experiments. The results are presented graphically in FIG. 1

example 2

Competitive Binding Study

[0036]This Example was carried out as described in Example 1, except that a 100-fold excess of unlabeled AGT was added at zero time. The cells were harvested at 5 min, and 4, 8 and 24 h. The results are presented graphically in FIG. 2

example 3

Competitive Displacement Study

[0037]This Example was carried out as described in Example 1, except that at 8 h, a 200-fold excess of unlabeled AGT was added to duplicate wells. The cells were harvested at 5 min and at 2 intervals through 18 h.

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Abstract

Disclosed is a method of screening a substance for angiotensinogen receptor-modulatory activity. The method includes the steps of contacting placental-derived cells with labeled angiotensinogen and a candidate substance; and then determining whether the candidate substance inhibits the binding of angiotensinogen to the placental-derived cells relative to a control wherein the placental-derived cells are contacted with angiotensinogen in the absence of the candidate substance.

Description

PRIORITY CLAIM[0001]This is a National Phase application of PCT Application Serial No. PCT / US02 / 10932, filed 5 Apr. 2002 which claims priority to provisional patent application Ser. No. 60 / 282,082, filed 6 Apr. 2001, the entire contents of both are incorporated herein by reference.FIELD OF THE INVENTION[0002]The invention is directed to the revelation of a placenta-specific renin-angiotensinogen receptor system in native human placental cells, and the use of cells exhibiting these newly-revealed receptors to assay putative drug candidates for their ability to modulate binding (reversibly, irreversibly, competitively, or non-competitively) at the placenta-specific renin-angiotensinogen receptor as it is displayed in native human placental cells.RELATED BACKGROUND[0003]The renin-angiotensin (RA) system is an enzymatic cascade. The first (and rate-controlling) reaction is a renin-catalyzed cleavage of angiotensinogen (AGT) to yield the decapeptide angiotensin I (Ang I). The second step...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): G01N33/53G01N33/567G01N33/50G01N33/74
CPCG01N33/5008G01N33/502G01N33/5044G01N33/74G01N2333/515G01N2500/02G01N2500/10
Inventor TEWKSBURY, DUANE A.
Owner MARSHFIELD CLINIC
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